2,3-bis-(benzamidomethylthio)-propanol



Patented Apr. 19, 1949 UNITED STATES TENT OFFICE 2,3-BIS-(BENZAMIDOMETHYLTHIO) PROPANOL No Drawing. Application June 13, 1946,Serial No. 676,594

1 Claim.

This invention relates to organic sulfides and their preparation. Forconvenience and simplicity, they are referred to herein as S-ethers ofcertain compounds having mercapto groups.

This is a continuation-in-part of my copending application Serial No.581,322, filed March 6, 1945, now U. S. Patent 2,449,332, forCompositions of matter.

It has recently been found that the compound 2,3-dimercapto-propanol isuseful in arsenic therapy, particularly against such substances as thechlorovinylchloroarsines. The usefulness of this compound in aqueousmedia, however, is limited because of its relatively lowWater-solubility and because of the instability of the aqueoussolutions.

An object of the present invention is to provide derivatives of2,3-dimercaptopropanol which are useful as systemic anti-arsenicals andas anti-vesicants. Another object is to provide derivatives of2,3-dimercaptopropanol which are more soluble in and more stable towardwater than that compound. A more specific object is to preparederivatives of 2,3-dimercaptopropanol in which mercapto hydrogen isreplaced by radicals having aromatic hydrocarbon amide groups. Otherobjects will appear hereinafter.

These objects are accomplished by the invention of aromaticS-amidomethyl ethers of 2,3- dimercaptopropanol and the processes forpreparing them which are described below. These S-ethers are derivativesof 2,3-dimercaptopropanol in which at least one of the mercaptohydrogens is replaced by the group R -oH,N

wherein R is hydrogen or a hydrocarbon radical and R is an aromatichydrocarbon radical.

In accordance with one method for preparing the aromatic S-amidomethylethers of this invention, an aromatic carboxylic acid amide havinghydrogen on the amido nitrogen atom is reacted with formaldehyde and2,3-dimercaptopropanol. This method is represented by the followingequation:

zolmooNin 2HCHO nsomcmsmomon 2 In a modification of the reactionillustrated above, an N-hydroxymethyl aromatic car-boxamide is firstprepared by reacting an aromatic carboxylic acid amide withformaldehyde, and the isolated N-hydroxymethyl aromatic amide thenreacted with 2,3-dimercaptopropanol. This method is illustrated by thefollowing equation:

In accordance with still another method, which is convenient for thepreparation of an anhydrous product, an N-(alkoxymethyl) aromaticcarboxamide is reacted in the presence of an acid catalyst with2,3-dimercaptopropanol. This method is illustrated by the followingequation:

In each of these methods thio-ethers in which only one mercapto hydrogenis replaced by an aromatic amidomethyl radical can be obtained byemploying equimolar proportions of the reactants.

The invention is illustrated in greater detail by the following example,in which the proportions of the ingredients are expressed as parts byweight:

Example Seventy parts of benzamide, 70 parts of water and 48 parts of37% aqueous formaldehyde are mixed with 2 parts of potassium carbonateas a catalyst and the reaction mixture allowed to stand at roomtemperature. In a few minutes N-methylolbenzamide begins to crystallizeout, a yield of the product having a melting point 92-95 C. beingobtained. A mixture of 60.4 parts of this material with 25 parts of 2,3-dimercaptopropanol in 82 parts of ethyl alcohol is warmed until a clearsolution is formed. Into this solution is then passed sufiicient dryhydrogen chloride to produce an acid reaction medium.

After standing at about 25 C. for about 15 hours, the mixture is warmedto 50-55 C. for thirty minutes and another 2.0 parts ofN-methylolbenzamide added. After standing again for 15 hours at 25 C. itis then poured into 400 parts of ice water and extracted with 150 partschloroform. The chloroform extract is dried with anhydrous calciumsulfate and the chloroform removed under reduced pressure. The residualmaterial is the bis-S-(benzamidomethyl) ether of 2,3-dimercaptopropanol,having an analysis a nitrogen content of 6.9% as compared to thecalculated amount of 7.2%.

So far as is known, any hydrocarbon primary or secondary aromaticcarboxamide, i. e., one having amido hydrogen, may be employed in theprocesses stated and illustrated above for preparing the S-amidomethylethers of the present invention. Thus, by appropriate choice of theamide, ethers may be obtained in which the radical R of the groupunsaturated, hydrocarbon radical and R is aromatic hydrocarbon radical.

The S-amidomethyl ethers of 2,3-dimercaptopropanol need not be isolatedfrom the reaction mixture for use in various applications, such as intherapeutic ointments, where they are employed in aqueous or watersoluble compositions. However, if it is desired to remove the smallamount of water introduced with the aqueous formaldehyde this can bedone by warming the reaction mixture under reduced pressure.

In the process illustrated by the example, involving the reaction ofN-methylolbenzamide with 2,3-dimercaptopropanol, an acid catalyst suchas hydrogen chloride is used. In this process, it is also preferred towarm the reaction mixture, e. g., to from 50-100 C. and to use anexcess, e. g., 25%, of the amide in the reaction mixture.

The aromatic S-amidomethyl ethers of 2,3- dimercaptopropanol have anumber of properties which make them of particular value for therapeuticapplications. In comparison to 2,3- dimercaptopropanol, theS-amidomethyl ether group increases the solubility in water and protectsthe thiol group from decomposition, the compound still possessing thedesired therapeutic and chemical reactivity. The aqueous solutions ofthe S-amidomethyl ethers can be adjusted to a pH ranging from mildlyalkaline to mildly acid without destroying stability. The highersolubility of the S-amidomethyl ethers, compared to that of2,3-dimercaptopropanol, enables the ethers to be incorporated in desiredconcentrations in water-soluble ointments for use in arsenic therapy.The S-amidomethyl ethers of 2,3- dimercaptopropanol are soluble inalcohols, e. g., methanol, ethanol, ethylene glycol and propyleneglycol, but are insoluble in hydrocarbon solvents. The S-amidomethylethers having hydrogen or low molecular weight hydrocarbon radicals onthe nitrogen atom are water soluble. The ethers having hydrocarbonradicals on the nitrogen atom are also soluble in ethyl ether.

Having thus described my invention, what I claim as new and wish tosecure by Letters Patent is:

A stable, water soluble anti-vesicant compound useful as ananti-vesicant and in arsenic and cadmium therapy consisting ofS-(benzamidomethyl) ether of 2,3-dimercaptopropanol.

FRANK K. SIGNAIGO.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,323,111 Austin et al June 29,1943 2,337,220 Albrecht et a1 Dec. 21, 1943 2.432.797 Peters et a1 Dec.16, 1947

